15,16-seco-19-nor progestins

ABSTRACT

15,16-Seco-19-nor progestins are provided which display elevated progestational activity with a minimum of ancillary hormonal activity. Processes for the preparation of the novel progestins are provided as are methods of use. A preferred method of use is in the suppression of ovulation in the human female.

ORIGIN OF THE INVENTION

This invention was made with U.S. government support under Contract No.N-01-HD-1-2809 awarded by the National Institutes of Health. The U.S.Government has certain rights in this invention.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a divisional of U.S. patent application Ser. No.07/647/298, filed Jan. 28, 1991 now U.S. Pat. No. 5,116,865, which is acontinuation-in-part of U.S. patent application Ser. No. 07/578,091,filed Sep. 5, 1990 now abandoned.

TECHNICAL FIELD

The present invention is in the field of steroid chemistry. Moreparticularly it relates to novel 15,16-seco-19-nor progestins, as wellas their preparation and methods of use. The novel compounds possesspotent progestational activity with a minimum of ancillary hormonalactivity.

BACKGROUND OF THE INVENTION

The use of substituted steroids for a number of therapeutic purposes,e.g., in the control of conception in female mammals in the regulationof the menstrual cycle, in conjunction with chemotherapy, and for anumber of other purposes, has been known for some time. See, forexample, G. Pincus et al., Science 124:890 (1956); J. Rock et al.,Science 124:891 (1956); G. Pincus, 1 of The Control of Fertility, (NewYork: Academic Press, 1965); and C. Djerassi, Science 151:3716 (1966).

The present invention is specifically directed to novel progestins,i.e., synthetic progesterone-like compounds which have no naturalcounterpart in the human body. These compounds find a wide range ofbeneficial applications in human therapy. Such applications include, forexample, in addition to suppressing ovulation in the human female,control of uterine bleeding, treatment of amenorrhea and dysmenorrhea,alleviation of endocrine disorders, and treatment of infertility.Examples of progestins and progestogens (i.e., naturally occurringprogesterone-like compounds) which have been used for these purposesinclude but are not limited to acetoxypregnenolone, anagestone acetate,chlormadinone acetate, desogestrol, dimethisterone, ethisterone,ethynodiol diacetate, fluorogestone acetate, gestodene,.hydroxymethylprogesterone and derivatives thereof (e.g.,hydroxymethylprogesteroneacetate),hydroxyprogesteroneand derivativesthereof (e.g., hydroxyprogesterone acetate and hydroxy- progesteronecaproate), levonorgestrel, lynestenol, melengestrol acetate,norethindrone, norethindrone acetate, norgesterol, normethisterone,pregnenolone, and progesterone.

Insofar as contraceptive methods and compositions are concerned,progestins are components of both the sequential and combination "pill"as well as long-acting injectables. Progestins are also administeredtogether with an estrogenic component for the treatment of climactericdisturbances. See, e.g.: U.S. Pat. No. 3,836,651 to Rudel et al.; U.S.Pat. No. 3,932,635 to Segre; U.S. Pat. No. 3,969,502 to Lachnit-Fixson;and U.S. Pat. No. 4,145,416 to Lachnit-Fixson et al. (Progestins havealso been used in oral contraceptive compositions that do not include anestrogenic component, as in U.S. Pat. No. 3,822,355 to Kincl et al. andin U.S. Pat. No. 4,066,757 to Pasquale. Indeed, such a formulation,containing norethindrone, is currently available and marketed under thetradename "Nor-Q.D." by Syntex Corporation, Palo Alto, Calif.)

While there are thus a number of progestins commercially available, withor without accompanying estrogenic compounds, there is a continuing needto improve efficacy and safety while minimizing unwanted side effects.Perhaps the most serious of these side effects is ancillary hormonalactivity, i.e., androgenic, estrogenic and antiestrogenic activities aswell as inhibition , of adrenocortical function. The following tableillustrates the androgenic, estrogenic, and antiestrogenic effects ofcurrently available contraceptive formulations:

                  TABLE 1                                                         ______________________________________                                                                     Androgenic                                       Pill        Progestin        Effect                                           ______________________________________                                        Ovcon-35    0.4 mg norethindrone                                                                           0.14                                             Brevicon/Modicon                                                                          0.5 mg norethindrone                                                                           0.17                                             Demulen 1/35                                                                              1 mg ethynodiol diacetate                                                                      0.21                                             Tri-Norinyl 0.5, 1.0, 0.5 mg 0.24                                                         norethindrone                                                     Ortho-Novum 7/7/7                                                                         0.5, 0.75, 1 mg  0.26                                                         norethindrone                                                     Ortho-Novum 10/11                                                                         0.5, 1 mg norethindrone                                                                        0.26                                             Triphasil/Tri-                                                                            0.5, 0.075, 0.12 mg                                                                            0.29                                             Levlen      levonorgestrel                                                    Norinyl and Ortho                                                                         1 mg norethindrone                                                                             0.34                                             1/35                                                                          Nordette/Levlen                                                                           0.15 mg levonorgestrel                                                                         0.47                                             Lo/Ovral    0.30 mg norgestrel                                                                             0.47                                             Loestrin 1/20                                                                             1 mg norethindrone                                                                             0.52                                                         acetate                                                           Loestrin 1/5/30                                                                           1.5 mg norethindrone                                                                           0.52                                                         acetate                                                           ______________________________________                                                                 Estrogenic                                           Progestin                Effect                                               ______________________________________                                        Norgestrel (Ovral, Lo/Ovral, Nordette,                                                                 0.00                                                 Tri-Levlen, Levlen)                                                           Norethindrone (1 mg) (Norinyl and Ortho-                                                               1.00                                                 Novum)                                                                        Norethindrone acetate (1 mg) (Norlestrin)                                                              1.52                                                 Ethynodiol diacetate (1 mg) (Demulen and                                                               3.44                                                 Ovulen)                                                                       Norethynodrel (2.5 mg) (Enovid)                                                                        20.80                                                ______________________________________                                                                 Anti-Estrogenic                                      Progestin                Effect                                               ______________________________________                                        Norethynodrel (2.5 mg) (Enovid)                                                                        0.0                                                  Ethynodiol diacetate (1 mg) (Demulen and                                                               1.0                                                  Ovulen)                                                                       Norethindrone (1 mg) (Norinyl and Ortho-                                                               2.5                                                  Novum)                                                                        Norgestrel (0.5 mg) (Ovral)                                                                            18.5                                                 Norethindrone acetate (1 mg) (Norlestrin)                                                              25.0                                                 ______________________________________                                    

In Table 1, androgenic activity is expressed in terms of milligrams ofmethyl testosterone equivalents per 28 days based on a rat ventralprostate assay. The estrogenic effect values derive from a comparativepotency test based on a rat vaginal epithelium assay. See R. C. Jones etal., "The Effects of Various Steroids on Vaginal Histology in the Rat,"in Fertil. Steril. 24:284 (1973). See also R. P. Dickey, ManagingContraceptive Pill Patients, 4th Ed., Durant, Okla.: CreativeInformatics, 1984.) The values for anti-estrogenic effect are calculatedusing the method of R. P. Dickey as set out in Managing ContraceptivePill Patients, 4th ed., Turant, Okla.; Creative Information, Inc.(1984).

The ancillary hormonal activity of the above formulations is believed tobe at least in part dose-related. Thus, it would be desirable to providea novel progestin which has potent progestational activity with aminimum of ancillary hormonal activity.

BACKGROUND ART

In addition to the references cited in the preceding section, thefollowing patents and publications also relate to compounds,formulations, syntheses and methods of use which may be relevant herein.

D-Ring Modified Steroids: J. S. Baran, J. Med. Chem. 10(6):1039-47(1967), describes the synthesis and chemistry of certain 15,16-secosteroids. P. F. Sherwin et al., in J. Med. Chem. 32(3):651-658 (1989),describe D-ring modification of androsta-1,4-diene-3,17-dione. U.S. Pat.No. 3,275,691 to Goldberg et al. describe polyhydrophenanthrenederivatives, i.e., in which the D-ring of the cyclopentanophenanthrenenucleus is open.

A-Ring Modified Steroids: U.S. Pat. Nos. 3,109,009 to Nomine et al. and3,471,550 to Uskokovic et al. describe A-ring "seco" compounds.

Synthetic Methods: U.S. Pat. No. 3,206,472 to Nagata et al. describe atotal synthesis of certain steroids which involves an intermediatehaving an "open" D-ring (compound XV in the patent).

SUMMARY OF THE INVENTION

It has now been discovered that certain novel 15,16-seco-19-norprogestins possess potent progestational activity, in some cases muchhigher than that of progesterone itself. The novel compounds presentlydisclosed and claimed also possess minimal ancillary hormonal activityand are thus far more desirable than the vast majority of progestinscurrently available. The present invention in one aspect provides these15,16-seco-19-nor progestins as new chemical compounds within theclasses defined by the following structural formulae (Ia), (Ib), (II),(IIIa), (IIIb), (IV), (Va), (Vb), (VI), (VII) and (VIII): ##STR1##

In these formulae:

R is hydrogen or an acyl group of the formula --(C═O)--Y;

Y is an organic substituent selected from the group consisting of alkyl,alkenyl, alkynyl, cycloalkyl, cycloalkylalkylene, haloalkyl, aryl,haloaryl and arylalkylene;

R' is hydrogen, alkyl of 1 to 12 carbon atoms, ##STR2##

R" is hydrogen or lower alkyl;

R¹ is selected from the group consisting of hydrogen, alkyl, alkenyl andalkynyl;

R² is selected from the group consisting of hydrogen, lower alkyl, andcyano; and

A, B and C represent optional double bonds. The compounds having anasymmetric carbon atom at position 17 are provided herein instereoisometrically pure form.

The invention also relates to a novel method of synthesizing certain ofthese compounds and to pharmaceutical compositions containing the novelcompounds.

The invention further encompasses methods of treatment involvingadministration of one or more of the above compounds to a patient toachieve desired progestational effects. These methods of treatmentinvolve administration of a composition containing a progestin asdescribed herein within the context of a dosing regimen effective toachieve the intended therapeutic or prophylactic result. In a preferredembodiment, the progestin is administered in combination with a separateestrogenic component for purposes of controlling fertility in amammalian female.

DETAILED DESCRIPTION OF THE INVENTION Definitions

In this specification and in the claims which follow reference will bemade to a number of terms which shall be defined to have the followingmeanings:

"Alkyl" refers to a branched or, unbranched saturated hydrocarbon groupof 1 to 24 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl,n-butyl, isobutyl, t-butyl, octyl, decyl, tetradecyl, hexadecyl,eicosyl, tetracosyl and the like. Preferred "alkyl" groups hereincontain 1 to 12 carbon atoms. "Lower alkyl" refers to an alkyl group ofone to six, more preferably one to four, carbon atoms.

"Alkenyl" refers to a branched or unbranched unsaturated hydrocarbongroup of 2 to 24 carbon atoms and one or more unsaturated carbon-carbonbonds, such as for example, ethenyl, 1-propenyl, 2-propenyl, 1-butenyl,2-isobutenyl, octenyl, decenyl, tetradecenyl, Δ8,11-heptadecadienyl,hexadecenyl, eicosenyl, tetracosenyl and the like. "Lower alkenyl"refers to an alkenyl group of two to six, more preferably two to four,carbon atoms

"Alkylene" refers to a difunctional saturated branched or unbranchedhydrocarbon chain containing from 1 to 6 carbon atoms, and includes, forexample, methylene (--CH₂), ethylene (--CH₂ --CH₂), propylene (--CH₂--CH₂ --CH₂ --), 2-methylpropylene [--CH₂ --CH(CH₃)--CH₂ --], hexylene[--(CH₂)₆ --] and the like.

"Alkynyl" refers to a branched or unbranched acetylenically unsaturatedhydrocarbon group of 2 to 24 carbon atoms such as ethynyl, 1-propynyl,2-propynyl, 1-butynyl, 2-butynyl, octynyl, decynyl, tetradecenyl,hexadecynyl, and the like "Lower alkynyl" refers to an alkynyl group oftwo to six, more preferably two to four carbon atoms.

"Acyl" refers to a group of the structure --(C═O)--Y, where Y is asdescribed herein. Acyl, therefore, includes such groups as, for example,acetyl, propanoyl (or propionyl), isopropanoyl, n-butanoyl (orn-butyryl), octanoyl, eicosanoyl, propenoyl (or acryloyl),2-methylpropenoyl (or methacryloyl), octanoyl, tetradecenoyl,eicosenoyl, tetracosenoyl, propynoyl, 2-butynoyl, n-2-octynoyl,n-2-tetradecynoyl, 2-chloropentanoyl, 2-chlorotetracosanyl,3-bromo-2-methacryloyl, benzoyl, 1-and 2- naphthoyl, phenylacetyl,6-phenylhexylenoyl, and the like. "Lower acyl" refers to a --(C═O)--Ygroup wherein Y is a lower alkyl of one to six, more preferably one tofour, carbon atoms such that the acyl contains a total of from two toseven, more preferably two to five, carbon atoms.

"Aryl" refers to a phenyl or 1- or 2-naphthyl group. Optionally, thesegroups are substituted with one to four, more preferably one to two,lower alkyl, lower alkoxy, hydroxy, and/or nitro substituents.

"Arylalkylene" refers to an aryl group as is defined herein which isattached to one end of an alkylene group as is defined herein. As usedherein, the other end of the alkylene group is attached to the carbon ofthe carbonyl group to form the acyl group.

"Cycloalkyl" refers to a saturated hydrocarbon ring group having from 3to 8 carbon atoms, and includes, for example, cyclopropyl, cyclobutyl,cyclohexyl, methylcyclohexyl, cyclooctyl, and the like.

"Cycloalkylalkylene" refers to a saturated hydrocarbon containing acycloalkyl group as is defined herein attached to one end of an alkylenegroup as is defined herein. The term includes, for example,cyclopropylmethylene, cyclobutylethylene,3-cyclohexyl-2-methylpropylene, 6-cyclooctylhexylene, and the like.

"Halo" or "halogen" refers to fluoro, chloro, bromo or iodo, usuallyregarding halo substitution for a hydrogen atom in an organic compound.Of the halos, chloro and bromo are generally preferred with chlorogenerally being the more preferred.

"Haloalkyl" refers to an "alkyl" group in which one to four, especiallyone of its hydrogen atoms, is substituted by a "halogen" group.

"Haloaryl" refers to an "aryl" group substituted with from one to fourhalogen groups.

"Optional" or "optionally" means that the subsequently described eventor circumstance may or may not occur, and that the description includesinstances where said event or circumstance occurs and instances in whichit does not. For example, "optionally substituted phenyl" means that thephenyl may or may not be substituted and that the description includesboth unsubstituted phenyl and phenyl wherein there is substitution.

In describing the location of groups and substituents, the followingnumbering system will be employed. ##STR3## This system is intended toconform the numbering of the cyclopentanophenanthrene nucleus to theconvention used by the IUPAC or Chemical Abstracts Service.

In these structures, the use of bold and dashed lines to denoteparticular conformation of groups again follows the IUPAC steroid-namingconvention. (The symbols "α" an "β" indicate the specific stereochemicalconfiguration of a substituent at an asymmetric carbon atom in achemical structure as drawn. Thus "α", denoted by a broken line,indicates that the group at the position in question is below thegeneral plane of the molecule as drawn, and "β", denoted by a bold line,indicates that the group at the position in question is above thegeneral plane of the molecule as drawn.)

In addition, the five- or six-membered rings of the steroid molecule areoften designated A, B, C and D as shown.

The Novel Compounds

The novel compounds provided herein are those defined by the structuralformulae (Ia), (Ib), (II), (IIIa), (IIIb), (IV), (Va), (Vb), (VI),(VII), and (VIII) above. Each of the novel compounds is "15,16-seco" inthat the D-ring of the cyclopentanophenanthrene nucleus is open at thosepositions, i.e., there is no bond between the C-15 and the C-16positions. The compounds are also designated "19-nor" herein to indicatethat a hydrogen atom rather than a carbon-containing substituent ispresent at 19-position. The preferred compounds within these groups areas follows.

In the groups of compounds defined by formulae (Ia) and (Ib), preferredcompounds are wherein R is hydrogen or an acyl group of the formula--(C═O)--Y, Y is selected from the group consisting of lower alkyl,cycloalkyl, phenyl optionally substituted with 1 or 2 lower alkyl, loweralkoxy, hydroxy and/or nitro substituents, and five- and six-memberedheterocyclic rings, R' is hydrogen, R" is hydrogen, and R¹ is hydrogenor lower alkynyl. Particularly preferred compounds of formulae (Ia) and(Ib) are wherein R is --(C═O)--Y, Y is selected from the groupconsisting of methyl, cyclobutyl, 3,5-dinitrophenyl, and furanyl, R¹ ishydrogen or --C.tbd.CH, R² is hydrogen, methyl or cyano, and Arepresents a doube bond. An exemplary compound within the class definedby formula (Ia) is17β-acetoxy-7α-methyl-15,16-seco-19-norandrosta-4-en-3-one.

Within the class of compounds encompassed by formula (II), preferredcompounds are those wherein R' is hydrogen, R" is hydrogen, R² ishydrogen, methyl, or cyano, and A represents a double bond.

With regard to formulae (IIIa) and (IIIb), preferred compounds that fallwithin the purview of these structures are those wherein R is hydrogenor an acyl group of the formula --(C═O)--Y, Y is selected from the groupconsisting of lower alkyl, cycloalkyl, phenyl optionally substitutedwith 1 or 2 lower alkyl, lower alkoxy, hydroxy and/or nitrosubstituents, and five-and six-membered heterocyclic rings, and R¹ ishydrogen or lower alkynyl. As with the compounds of formulae (Ia) and(lb), particularly preferred compounds of formulae (IIIa) and (IIIb) arewherein R is --(C═O)--Y, Y is selected from the group consisting ofmethyl, cyclobutyl, 3,5-dinitrophenyl, and furanyl, R¹ is hydrogen or--C.tbd.CH, R² is hydrogen, methyl or cyano, and B represents a doublebond.

Within the class of compounds encompassed by formula (IV), preferredcompounds are those wherein R² is hydrogen, methyl, or cyano, and Brepresents a double bond.

With regard to compounds defined by formulae (Va) and (Vb), preferredcompounds are those wherein R is hydrogen or an acyl group of theformula --(C═O)13 Y, Y is selected from the group consisting of loweralkyl, cycloalkyl, phenyl optionally substituted with 1 or 2 loweralkyl, lower alkoxy, hydroxy and/or nitro substituents, and five- andsix-membered heterocyclic rings, and R¹ is hydrogen or lower alkynyl. Aswith the compounds of formulae (Ia), (Ib), (IIIa) and (IIIb),particularly preferred compounds of formulae (Va) and (Vb) are wherein Ris --(C═O)--Y, Y is selected from the group consisting of methyl,cyclobutyl, 3,5-dinitrophenyl, and furanyl, R¹ is hydrogen or--C.tbd.CH, and R² is methyl or cyano.

Preferred compounds defined by formula (VI) are wherein R² is hydrogen,methyl or cyano.

Preferred compounds defined by formula (VII) are wherein R² is hydrogenor methyl, more preferably hydrogen, while preferred compounds Withinthe scope of formula (VIII) are wherein R' and R" are hydrogen.

Process for Preparation

The compounds of the invention may be prepared in high yield usingrelatively simple, straightforward methods as exemplified in theexperimental section herein.

Synthesis of representative compounds of formulae Ia and Ib isdescribed, inter alia, in Examples 1, 2, 3 and 5 below. As illustratedin Schemes and 2 below, a 1,3,5(10)-triene-17-one is generally used asthe starting material, working through 17-hydroxyl intermediates toobtain the desired product. Preparation of a III-type compound, i.e., a3β,17β-dihydroxy material, is described exemplified in Example 4, andinvolves synthesis from a 17β-acetoxy-3-one. Compounds of formula II maybe prepared by conversion of the 17-hydroxy moiety to a 17-one asdescribed in Example 7 (Scheme 6). The 1,3,5(10)-trienes of V and VI maybe derived as illustrated in Scheme 1.

Th method of synthesizing a compound of formula ##STR4## which comprisesreacting a starting material of formula ##STR5## with methylmagnesiumbromide in the presence of a lower alkyl amine is considered to be noveland represents an aspect of the present invention. In the aboveformulae, X is a hydroxyl protecting group, preferably an aromaticspecies such as benzyl, Z is lower alkyl, e.g., methyl, and R² ishydrogen, lower alkyl, or cyano. In a preferred embodiment, the loweralkyl amine is triethyl amine. This reaction is exemplified in section(a.) of Example 1.

Utility and Administration

The compounds disclosed and claimed herein are useful for achievingtherapeutic or prophylactic progestational effects in a patient. Asnoted above, progestins, including the present compounds, are useful forthe following purposes: suppressing ovulation in the human female;controlling uterine bleeding; treating amenorrhea and dysmenorrhea;alleviating endocrine disorders; in conjunction with chemotherapy; andin treating infertility.

In the preferred embodiment, the present compounds are used either aloneor in combination with one or more estrogenic components in acontraceptive composition, within the context of a dosing regimeneffective to suppress ovulation. A number of such dosing regimens havebeen developed and are well-known in the art. So-called monophasicdosing regimens involve a constant daily dose of a progestin and anestrogen for 21 days of the menstrual cycle, while a biphasic regimeninvolves two 10/11 day dosing periods in which a lower dose ofprogestogen is administered throughout the first period, followed byadministration of a higher dose throughout the second period. Thecurrently popular triphasic regimen involves stepped-up administrationof the progestogen component throughout the three phases of the cycle,with a higher dose of estrogen administered in the middle phase. Asequential, nonphasic regimen is also known; in such a regimen, theprogestogen is only administered for five days at the end of the cycle.Relative quantities of estrogen and progestogen in these compositionsvary. Typically, "combination" pills contain from about 25-50 microgramsestrogen and 0.3 to 3.0 mg progestin.

Suitable estrogens useful in contraceptive compositions containing thepresent progestins include estradiol and its esters, e.g., estradiolvalerate, cyprionate, decanoate and acetate, as well as ethinylestradiol. The progestin may also be administered without an estrogeniccomponent for purposes of suppressing ovulation in a human female.

Administration of the active compounds described herein can be via anyof the accepted modes of administration of therapeutic agents. Thesemethods include parenteral, transdermal, subcutaneous and other systemicmodes. For those compounds herein which are orally active, oraladministration is the preferred mode. For those compounds which are notorally active, administration in the form of a long-acting injectablecomposition is preferred.

Depending on the intended mode of administration, the compositions maybe in the form of solid, semi-solid or liquid dosage forms, such as, forexample, tablets, suppositories, pills, capsules, powders, liquids,suspensions, or the like, preferably in unit dosage forms. suitable forsingle administration of precise dosages. The compositions will includea conventional pharmaceutical excipient and one or more of the presentprogestins or pharmaceutically acceptable salts thereof and, inaddition, may include other medicinal agents, pharmaceutical agents,carriers, adjuvants, diluents, etc.

The amount of active compound administered will, of course, be dependenton the subject being treated, the subject's weight, the manner ofadministration and the judgment of the prescribing physician. However,an effective dosage amount for purposes of suppressing ovulation isgenerally in the range of about 0.2-20 mg/kg/day.

For solid compositions, conventional nontoxic solids include, forexample, pharmaceutical grades of mannitol, lactose, starch, magnesiumstearate, sodium saccharin, talc, cellulose, glucose, sucrose, magnesiumcarbonate, and the like may be used. The active compound as definedabove maybe formulated as suppositories using, for example, polyalkyleneglycols, for example, propylene glycol, as the carrier. Liquidpharmaceutically administrable compositions can, for example, beprepared by dissolving, dispersing, etc. an active compound as definedabove and optional pharmaceutical adjuvants in an excipient, such as,for example, water, saline, aqueous dextrose, glycerol, ethanol, and thelike, to thereby form a solution or suspension. If desired, thepharmaceutical composition to be administered may also contain minoramounts of nontoxic auxiliary substances such as wetting or emulsifyingagents, pH buffering agents and the like, for example, sodium acetate,sorbitan monolaurate, triethanolamine sodium acetate, triethanolamineoleate, etc. Actual method of preparing such dosage forms are forexample, see Remington's Pharmaceutical Sciences, Mack PublishingCompany, Easton, Pa., 15th Edition, 1975. The composition or formulationto be administered will, in any event, for purposes of suppressingovulation, contain a fertility-controlling amount of the desiredprogestin(s), i.e., an amount effective to achieve the desired fertilitycontrol in the female subject being treated.

For oral administration, i.e., of any of the present compounds which maybe orally active, a pharmaceutically acceptable nontoxic composition isformed by the incorporation of any of the normally employed excipientsdescribed above. Such compositions take the form of solutions,suspensions, tablets, pills, capsules, powders, sustained-releaseformulations and the like. Such compositions may contain 1%-95% activeingredient, preferably 1-10%, and will preferably contain an estrogeniccomponent as noted above.

Parenteral administration, if used, is generally characterized byinjection, either subcutaneously, intramuscularly or intravenously.Injectables can be prepared in conventional forms, either as liquidsolutions or suspensions, solid forms suitable for solution orsuspension in liquid prior to injection, or as emulsions. Suitableexcipients are, for example, water, saline, dextrose, glycerol, ethanolor the like. In addition, if desired, the pharmaceutical compositions tobe administered may also contain minor amounts of nontoxic auxiliarysubstances such as wetting or emulsifying agents, pH buffering agentsand the like, such as, for example, sodium acetate, sorbitanmonolaurate, triethanolamine oleate, etc.

A more recently revised approach for parenteral administration employsthe implantation of a slow-release or sustained-release system, suchthat a constant level of dosage is maintained. See, e.g., U.S. Pat. No.3,710,795, which is incorporated herein by reference.

It is to be understood that while the invention has been described inconjunction with the preferred specific embodiments thereof, that theforegoing description as well as the examples which follow are intendedto illustrate and not limit the scope of the invention. Other aspects,advantages and modifications within the scope of the invention will beapparent to those skilled in the art to which the invention pertains.

EXAMPLES

The following Examples 1 through 17 illustrate sequentially thesynthesis of various compounds of the invention.

Example 1

This example describes the preparation of 17β-acetoxy-7α-methyl-15,16-seco-19-norandrosta-4-en-3-one (12) as outlined inScheme 1. ##STR6##

(a.) Svnthesis of3-Benzyloxy-16.17-seco-16-norestra-1,3,5(10)-trien-17-oic Acid MethylEster (1) ##STR7##

A solution of 7.6 g of3-benzyloxy-16,17-secoestra-1,3,5(10)-triene-16,17-dioic16-t-butylperester 17-methyl ester in 300 ml of freshly distilled cumene waspurged with nitrogen for 1 hr. The cumene solution was then refluxed for1 hr and the solVent removed in vacuo to yield 7.7 g of a semi-solidresidue. Chromatography of 7.5 g of this residue on 500 g of silica geland elution with benzene afforded 4.4 g of pure 1. Recrystallizationfrom methanol afforded an analytical sample, mp 97°-99° C., lit mp96°-98° C. (M. A. Bierefeld and R. Oslapas, J. Med. Chem. 12, 192,1969).

(b.) Synthesis of 3-Benzyloxy-15.16-secoestra-1,3,5,(10)-triene-17-one(2)

To a solution of 13.5 of 1 in 800 ml of dry THF (distilled frommethylmagnesium bromide) was added 8.3 ml of dry triethylamine. (Drytriethylamine was prepared by passing it through a column of Woelmalumina activity grade super I.) To the THF solution was added dropwise82 ml of 2.9 M methylmagnesium bromide in ether. The reaction wasallowed to stir at room temperature for 4 hr. TLC indicated ester (2)remained, so an additional 41 ml of 2.9 M methylmagnesium bromide wasadded. The reaction was stirred for an additional 18 hr at roomtemperature, then poured slowly into 4% hydrochloric acid, and extractedwith ether. The ether solution was separated and washed with 4%hydrochloric acid, 4% sodium hydroxide, and water. The ether solutionwas dried over sodium sulfate and evaporated at reduced pressure toyield 14.1 g of product 2, which was purified by thick-platechromotography.

Anal. High-Resolution Mass Spec. for C₂₅ H₃₀ O₂ Calcd.: 362.2246; found:362.2233. NMR and IR spectra were consistent with the assignedstructures.

(c.) Synthesis of 3-Hydroxy-15,16-secoestra-1,35(10)-triene-17-one (3)

To a solution of 14.1 g of 2 in 800 ml of absolute ethanol was added 1.0g of 5% palladium on carbon. The suspension was hydrogenated at roomtemperature and at atmospheric pressure for 18 hr. The suspension wasfiltered through celite to remove the palladium on carbon catalyst. Theethanol was evaporated at reduced pressure to yield 3. Recrystallizationfrom methanol afforded 8.1 g of an analytical sample of 3; mp 181.5° C.

Anal. calcd. for C₁₈ H₂₄ O₂ :C, 79.37; H, 8.88. Found: C, 79.37; H,8.93.

(d.) Synthesis of 3-Methoxy-15.16-secoestra-1.3,5,(10)-triene-17-one (4)

To a solution of 6.5 g of 3 in 600 ml of acetone was added 12.6 g ofpotassium carbonate and 2.1 ml of methyl iodide. The reaction wasallowed to stir at room temperature for 48 hr. Approximately half of thevolume of acetone was evaporated at reduced pressure. The remainingsuspension was poured into water and extracted with ether. The ethersolution was washed with water, dried over sodium sulfate, andevaporated at reduced pressure to yield 6.2 g of Recrystallization frommethanol afforded an analytical sample of 4; mp 64° C.

Anal. calcd. for C₁₉ H₂₆ O₂ : C79.68; H, 9.15. Found: C, 79.26; H, 9.16.

(e.) Synthesis of 3-Methoxy-17β-hydroxy-15.16-secoestra-1,3,5(10)-triene(5)

To a solution of 25.0 g of 3-methoxy-15,16-secoestra-1,3,5(10)-triene-17-one (4) in 1.0 L of methanol at 0°-5° (ice bath)was added portion-wise 6.61 g of sodium borohydride. The reactionmixture was stirred at 0°-5° for 1.8 hr and then quenched with the slowaddition of 1.5 ml of acetic acid. The reaction mixture was poured into3.0 L of water. The milky suspension was extracted with ether. The ethersolution was washed with water, dried over sodium sulfate and evaporatedat reduced pressure to afford 24.8 g of 5. The crude product, whenanalyzed by NMR and thin-layer chromatography (TCL)-25%tetrahydrofuran/hexane--indicated the presence of two C-17 isomers--themajor product being 5. An analytical sample of 5 was obtained byrecrystallization from acetone/hexane, mp 84°-85° C.

Anal. Calcd. for C₁₉ H₂₈ O₂ : C, 79.12; H, 9.78. Found: C, 79.31; H,9.66.

(f.) Synthesis of 3-Methoxy-17β-hydroxy-15,16-secoestra-2,5(101-diene(6)

To a solution of 2.0 L of ammonia at -78° C. (dry ice-acetone) Was added12.04 g of lithium wire washed with hexane. After 1.0 hr, 24.9 g of (5)in a mixture of 300 ml of ether and 100 ml of absolute ethanol was addedto the dark blue ammonia lithium solution at -78° C. The reaction wasstirred at -78° C. for an additional 2 hr while the dark blue colorremained. The reaction was quenched with the slow addition of 200 ml ofethanol. The reaction was allowed to warm to room temperature, and theammonia was evaporated over 18 hr. The white solid residue was dissolvedin ether and water. The organic phase was separated and washed withwater, dried over sodium sulfate, and evaporated at reduced pressure toyield 24.8 g of product 6.

(g.) Synthesis of 17β-Hydroxy-15.16-seco-19-norandrosta-4-en-3-one (7)

To a suspension of 24.8 g of 6 in, 500 ml of methanol was added dropwisei.0 ml of concentrated hydrochloric acid. The reaction was stirred atroom temperature for 18 hr. The methanol was evaporated to half itsvolume at reduced pressure and then poured into water. The milkysuspension was extracted with ether, and the ether solution was washedwith water, dried over sodium sulfate, and evaporated to dryness atreduced pressure to afford 26.2 g of crude product 7. The crude product7 was recrystallized from ether to yield pure 7 mp 155°-156° C.

Anal. High Res. Mass Specs for C₁₈ H₂₈ O₂ : Calcd., 276.2089; found,276.2086.

Anal. Calcd. for C₁₈ H₂₈ O_(2;) C, 78.21; H, 10.21. Found: C, 78.33; H,10.00.

(h.) Svnthesis of 17β-Acetoxv-15.16-seco-19-norandrosta-4-en-3-one (8)

A solution of 10.0 g of 7 in 30 ml of pyridine and 10.0 ml of aceticanhydride was stirred at room temperature for 18 hr. The reactionmixture was poured into ether/water and the organic phase was separated.The aqueous phase was extracted several times with ether. The ethersolutions were combined, washed with water, 4% hydrochloric acid, andwater. The ether solution was dried over sodium sulfate and evaporatedat reduced pressure to yield 11.42 g of 8. An analytical sample wasobtained by recrystallization from methanol, mp 143°-145° C.

Anal. High Res. Mass Spec. for compound 8 C₂₀ H₃₀ O₃ : Calcd., 318.2195;found, 318.270.

Calcd. for C₂₀ H₃₀ O₃ : C, 75.43; H, 9.50. Found: C, 75.14; H, 9.33.

(i.) Synthesis of 3,17β-diacetoxy-15,16-seco-19-norandrosta-3,5-diene(9)

A solution of 11.32g of 8 in 5.0 ml of acetic anhydride containing 80.0ml of freshly distilled acetyl chloride was refluxed for 4.0 hr. Thesolvent was removed at reduced pressure and the resulting oil wastriturated with cold aqueous sodium bicarbonate and ice-water. Thetrituration, at first, gave an oil that on standing, afforded a whitecrystalline solid, which was filtered and air-dried to afford 11.7 g of9. An analytical sample was obtained by recrystallizing 9 from acetone,mp 164°-167° C.

Anal. High Res. Mass Spec. for compound 9, C₂₂ H₃₂ O₄ : Calcd.,360.2300; found, 360.2311.

(j.) Synthesis of 17β-Acetoxv-15,16-seco-19-norandrosta-4.6-dien-3-one(10)

To a solution of 10.78 g of 9 in 650.0 ml of acetone and 120.0 ml watercontaining 76.5 ml acteic acid, 6.4 ml pyridine, and 14.07 g of sodiumacetate at 0°-5° C. (ice-water bath) was added 5.83 g of recrystallizedN-bromosuccinimide. The N-bromosuccinimide had been previouslyrecrystallized from water and dried under vacuum over conc. sulfuricacid for five days. The reaction was stirred at 0°-5° C. for 3 hr whilethe flask was totally shielded from light. The reaction mixture waspoured into cold saturated sodium chloride and extracted with ether. Theether solution was washed with saturated sodium chloride, dried oversodium sulfate, and evaporated at reduced pressure to afford 76.4 g ofbromoenone. The bromoenone was used immediately without purification inthe subsequent dehydrobromination reaction. The bromoenone (16.4 g) wasdissolved in 200.0 ml of dimethylformamide and added to a boilingsuspension of 10.2 g of lithium bromide and 10.2 g of lithium carbonatein 400.0 ml of dimethylformamide. The suspension was refluxed for 1.0 hrand then cooled. The suspension was filtered, the filtrate was pouredinto an ice-water solution, and the mixture was extracted with ether.The ether solution was washed with 4% sodium hydroxide, water andsaturated sodium chloride. The ether solution was dried over sodiumsulfate and evaporated at reduced pressure to yield I0.2 g of 10. Ananalytical sample was obtained by recrystallization from methanol, mp162°-163° C.

Anal. High Res. Mass Spec. for compound 10, C₂₀ H₂₈ O₃ :Calcd.,316.2058; found, 316.2038.

(k.) Synthesis of17β-Acetoxy-7α-methyl-15,16-seco-19-norandrosta-5-en-3-one (11)

To a suspension of 11.82 g of copper (I) iodide in 360.0 ml of anhydrousether at 0°-5° C. (ice-water bath) was added, via a syringe, 82.6 ml of1.55 M methyllithium in ether. The resulting dark brown-grey solutionwas stirred at 0°-5° C. for 15 min. A solution of 4.0 g of17β-acetoxy-15,16-seco-19-norandrosta-4,6- dien-3-one in 120.0 ml of drytetrahydrofuran (distilled from methylmagnesium bromide) was addeddropwise (25 min) to the reaction mixture. The reaction mixture wasstirred for an additional 0.5 hr at 0°-5° C. and then poured into coldaqueous saturated ammonium chloride, with vigorous stirring.Approximately 1.0 L of benzene was added and stirring was continued for0.5 hr. The organic layer was separated and washed with additionalammonium chloride. The benzene solution was separated and dried overmagnesium sulfate and evaporated to dryness at reduced pressure, toafford 4.1 g of crude product. A portion of the residue was purified bythick-plate chromatography on silica gel plate and developed with 25%tetrahydrofuran in hexane to afford pure 11.

Mass Spec. for compound 11, C₂₁ H₃₂ O₃ : Calcd., 332; found, 332.

(l.) Synthesis of17β-Acetoxv-7α-methvl-15,16-seco-19-norandrosta-4-en-3-one (12)

A solution of crude 11 was dissolved in 500 ml of benzene containing acatalytic amount of PTSA. The solution was heated on a steam bath for0.5 hr. The reaction was cooled to room temperature and then poured intowater. The organic layer was separated and washed with water, dried overmagnesium sulfate, and evaporated at reduced pressure to afford 1.2 g ofcrude product. The crude product was purified by HPLC using 12% ethylacetate/hexane as the eluant to afford pure 12. An. analytical samplewas obtained by recrystallization from hexane, mp 105°--106° C.

Anal. Calcd. for C₂₁ H₃₂ O₃ ; C, 75.86; H, 9.70. Found: C, 75.78; H,9.34.

Example 2

This example describes an alternative pathway to3-methoxy-15,16-secoestra-1,3,5,(10)-triene-17-one (4) as illustrated inScheme 2. ##STR8##

Oxidative cleavage of ring D of 3-methylestrone (13) with sodiummethoxide and iodine under aeration yielded the diester 14 and a mixtureof monoacids 15 and 16. The mixture of acids was esterified in methanolcontaining sulfuric acid to complete the conversion to diester 14 in anoverall combined yield of 95%. Selective saponification of 14 withmethanolic KOH gav,e the crude monoester 16. Treatment of 16 with anexcess of oxalyl chloride in benzene afforded the crude acid chloride17. Treatment of 17 with t-butyl hydroperoxide in benzene with pyridinefurnished the perester 18 in good yield. Decomposition of the peresterin boiling cumene gave the decarboxylated product 19. Attempts tosynthesize the methyl ketone 4 via Corey's protocol were thwarted:addition of methylsulfinyl carbanion to the methyl ester 19 followed byreductive cleavage of the resulting β-keto sulfoxide with aluminumamalgam were unsuccessful. Therefore, for the conversion of ester 19 tothe methyl ketone 4, Kikkawa's observation (I. Kikkawa et al., Synthesis11:877 (1980)) that Grignard reagents react with esters in the presenceof a tertiary amine to give alkyl ketone without overreaction toalcohols was utilized. By this method, 4 was obtained in high yield bytreating the methyl ester 19 with an excess of an equimolar admixture ofmethylmagnesium bromide and triethylamine, as follows.

To an anhydrous solution of the ester (19, 50 g) and triethylamine (45ml) in tetrahydrofuran (500 ml) under nitrogen, was added dropwise asolution of methyl magnesium bromide in ether (1.0 mole). (Drytriethylamine was prepared by passing it through a column of Woelmalumina, activity grade Super I.) The reaction mixture was stirred atambient temperature, under nitrogen, overnight, and then pouredcautiously into a mixture of concentrated hydrochloric acid (50 ml) andcrushed ice (˜1000 ml). Ice and concentrated hydrochloric acid wereadded until the mixture was ˜pH 4 and the magnesium salts weredissolved. The aqueous and tetrahydrofuran layers were separated and thetetrahydrofuran was evaporated in vacuo. The residue was taken intoether, washed successively with water, saturated sodium bicarbonatesolution, water, and brine, dried over Na₂ SO₄, and filtered.Evaporation of solvent gave the crude methyl ketone (4, 44.8 g).The,pure ketone was obtained by dissolving the residue in methanol andthen cooling it in a dry ice-isopropanol bath. The methanol was thendecanted and the residue was again dissolved in methanol. The methylketone (4) crystallized in both the decantate (4.6 g) and the residue(25.9 g). The residue was crystallized once again to give the puremethyl ketone (16.1 g, mp 63.5°-65° C.). The residue was purified byhexanes:ethyl acetate, 95:5, 200 ml/min). After in vacuo evaporation ofthe chromatography solvent, the residue was crystallized from methanolto give the pure ketone (4, 7.8 g, 28.7 g total for the reaction).

Example 3

This example describes a procedure analogous to the reaction set forthin Example 1, part (a), but involves the preparation of a compoundhaving a methoxy group at the 3-position rather than a benzyloxy group.##STR9##

3-Methoxy-16,17-secoestra-1,3,5(10)-trien-17-oic acid methyl ester (19)

A solution of 83.1 g of3-methoxy-16,17-secoestra-1,3,5(10)-triene-16,17-dioic16-t-butylperester 17-methyl ester (18) (obtained by the. method of M. A.Bierefeld and R. Oslapas, suora, in freshly distilled cumene was purgedwith nitrogen for 1 hr, then refluxed for 1 hr. The cumene was removedunder reduced pressure to give 83.1 g of a semi-solid residue. Theresidue was triturated with methanol and filtered to remove 14.7 g ofdicumene as a white crystalline solid. The remaining material containingthe ester was purified by preparative liquid chromatography PrepPakcolumn, hexane:ethyl acetate, 95:5, 200 ml/min). Thee fractions werecollected containing: (i) dicumene (7.6 g); (ii) the desired ester (49.6g); and (iii) a slightly more polar product later established by NMR tobe the tert-butyl ether (4.5 g). Evaporation of chromatography solventsyielded the ester as a white solid which was used without furtherpurification. A total of 129.8 g of the ester was obtained (54% yield).An analytical sample was obtained by recrystallization from methanol togive the pure ester 19, mp 55°-57° C.

Anal Calcd. for C₁₉ H₂₆ O₃ C, 75.46; H, 8.67. Found: C, 75.77; H, 8.64.

Example 4

This example illustrates the preparation of3β,17β-dihydroxy-7α-methyl-15,16-seco-19-norandrosta-5-en-3β-ol (22)according to Scheme 3: ##STR10##

(a.) 17β-Acetoxy-7α-methyl-15,16-seco-19-nor-androsta-5-en-3β-ol (20)and 17β-acetoxy-7α-methyl-15,16-seco-19-norandrosta-5-en-3α-ol (21)

To a solution of 1.80 g of 11 in 180 ml of methanol at 0°-5° C.(ice-water bath) was added 1.80 g of sodium borohydride in 0.200 gportions. The reaction was stirred at 0-5° C. for 20 min, then pouredinto ice water and extracted with ether. , The ether solution was washedwith saturated sodium chloride, dried over magnesium sulfate, andevaporated at reduced pressure to afford 1.92 g of a mixture of 20 and21. The mixture was separated on a Waters preparative HPLC silica gelcolumn, using 15% ethyl acetate/hexane as the solvent to afford 0.413 gof pure and 0.250 g of pure as glasses.

Anal. Hi. Res. Mass Spec. for compound 20, C₁₂ H₃₄ O₃ : Calcd.,334.2476; found, 334.2508. For compound 21: Calcd., 334.2476; found,334.2510.

(b.) 3β,17β-Dihydroxy-7α-methyl-15,16-seco-19-norandrosta-5-en-3β-ol(22)

A suspension of 0.413 g of 20 in 100 ml of 10% potassium hydroxide inmethanol was stirred at room temperature for 18 hr. The reaction waspoured into water and extracted with ether. The ether solution waswashed with water, dried over magnesium sulfate, and evaporated atreduced pressure to afford 0.301 g of 22. Purification by chromatographyon preparative thick plate developed in 25% tetrahydrofuran/hexane andrecrystallization from acetone afforded pure 22; mp 186°-187° C.

Anal. Hi. Res. Mass Spec. for compound 22, C₁₉ H₃₂ O₂ : Calcd.,292.2402; found, 292.2386.

Example 5

This example describes the synthesis of17β-acetoxy-7α-cyano-15,16-seco-19-norandrosta-4-en-3-one(23) asillustrated by Reaction Scheme 4 ##STR11##

17β-Acetoxy-7α-cyano-15,16-seco-19-norandrosta-4-en-3-one (23)

To a solution of 0.26 g of 10 in 11 ml of dry THF (dried by distillationfrom methylmagnesium bromide and storage over molecular sieves (Aldrich4 Å)) under argon was added 2.4 ml of a i.8 M solution ofdiethylaluminum cyanide (in toluene). The mixture was stirred at roomtemperature under argon for 1 hr and then added to a 2 N sodiumhydroxide solution. The cloudy solution was extracted with ether. Thecombined ether extract was washed with 2 N sodium hydroxide solution andwater and then dried over sodium sulfate. The ether solution wasevaporated to dryness at reduced pressure. The residue (0.263 g) waschromatographed on a Waters 500 preparative HPLC equipped with a1-inch-diameter stainless steel column. The product was eluted with 5%ethyl acetate/chloroform. This procedure afforded 0.112 g of pure 23.Trituration with ether gave an analytical sample, mp 194°-196° C.

Anal. Calcd. for compound 23, C₂₁ H₂₉ NO₃ : Calcd.: C, 73.44; H, 8.51;N, 4.08. Found: C, 73.19; H, 8.50; N, 4.03.

Example 6

This example describes the preparation of17β-acetoxy-7α-methyl-15,16-seco-19-nor-5 α-androsta-3-one(24) accordingto Scheme 5: ##STR12##

To 100 ml of ammonia at -78° C. (dry ice-acetone) was added 0.076 g oflithium wire washed with hexane. After 1.0 hr. 0.352 g of 12 in 30 ml ofdry THF (distilled from methylmagnesium bromide and stored overmolecular sieves, Aldrich 4 Å) was added to the dark blueammonia-lithium solution at -78° C. The reaction was stirred at -78° C.for 2 hr while the dark blue color remained. The reaction was thenquenched by the slow addition of 5 ml of 1,2-dibromoethane. After thecolor of the reaction mixture had turned to white, the cooling bath wasremoved and the ammonia was allowed to evaporate overnight. The residuewas dissolved in ether/water. The ether solution was washed with waterseveral times, dried over magnesium sulfate, and evaporated to drynessat reduced pressure to yield 0.401 g of a mixture. NMR analysisindicated that the mixture had C-17 hydroxy (25) and C-17 acetoxy (24)functionalities.

The reaction mixture (0.401 g) was dissolved in 1.0 ml of pyridinecontaining 1.0 ml of acetic anhydride. The solution was stirred at roomtemperature for 18 hr and then poured into water and extracted withether. The ether solution was washed with water, 4% hydrochloric acid,and water. The ether solution was then dried over magnesium sulfate andevaporated to dryness at reduced pressure to yield 0.409 g of crudeproduct 24. Chromatography of crude product 24 on preparative HPLC,using a 1-in. stainless steel column packed with normal-phase silica geland eluting with 10% ethyl acetate/petroleum ether (bp 35°-60° C.),afforded 0.140 g of an analytical sample of17β-acetoxy-7α-methyl-15,16-seco-19-nor-5α-androsta-3-one 24; mp121°-122° C.

Anal. Hi. Res. Mass Spec. for compound 24, C₂₁ H₃₄ O₃ : Calcd. (C₁₉ H₃₀O, M-HOAc), 274.2297; found, 274.3316. Also Calcd. (C₁₇ H₂₇ O, M-C₄ H₇O₂), 247.2075; found, 247.2062.

Mass Spec. using chemical ionization mass spectrum analysis for C₂₁ H₃₄O₃ : Calcd. 334; Found, 334.

Example 7

This example sets forth the synthesis of15,16-seco-5α-19-norandrosta-3,17-dione (27) according to Scheme 6:##STR13##

To a three-neck round-bottom flask, equipped with a mechanical stirrerand dry ice condenser, was added 900 ml of ammonia while the flask wasbeing cooled in a dry ice/acetone bath. To the ammonia was added 3.02 gof lithium wire (washed free of mineral oil with hexane). The solutionturned dark blue as the lithium dissolved. After the addition of lithiumwas completed, the reaction was stirred an additional 1.0 hr at -78° C.To the dark blue solution was added 6.0 g of enone 7 in 150 ml of adioxane ether solution (1:1). After stirring for 2.0 hr at -78° C., thereaction was quenched with the slow addition of sat. NH₄ Cl. Thereaction was allowed to warm to room temperature and the ammoniaevaporated overnight. The white solid residue was dissolved in Et₂ O/H₂O. The aqueous phase was separated and again washed with ether. The Et₂O. solutions were combined and washed with H₂ O. The Et₂ O solutionswere dried over MgSO₄ and evaporated at reduced pressure to afford 5.8 gof a crude mixture.

To a solution of 5.8 g of crude mixture containing 26 in 400 ml ofacetone, cooled to 0°-5° C. (ice-water bath) with nitrogen bubbled intothe acetone, was added dropwise Jones reagent until the solution's colorremained a dark brown-orange. The reaction was stirred an additional 10min at 0.5° C and then quenched with the slow addition of 10 ml ofisopropyl alcohol. The acetone was evaporated at reduced pressure, andthe residue was dissolved in ether and water. The ether solution wasseparated and the aqueous phase was again extracted with ether. Theether solutions were combined and washed with water, dried over sodiumsulfate, and evaporated at reduced pressure to yield 6.3 g of crudeproduct. The crude product was chromatographed on 300 g of silica gel,90-200 mesh, two-inch column, and eluted with 20% tetrahydrofuran/hexaneto afford 4.1 g of pure 15,16-Seco-5α-19-norandrosta-3,17-dione (27). Ananalytical sample was obtained by recrystallization from ether/hexane,mp 76°-78° C.

Anal. Hi. Res. Mass Spec. for compound 27, C₁₈ H₂₈ O₂ : Calcd.,276.2089; found, 276.2081. Calcd.: C, 78.21; H, 10.21. Found: C, 78.20;H, 9.95.

Example 8

This example describes the synthesis of15,16-secoestra-1,3,5(10)-triene,3-methyl ethyl (28) and15,16-secoestra-1,3,5-trien-3-ol (29) as outlined in Scheme 7: ##STR14##

(a.) 15,16-Secoestra-1,3,5(10)-triene, 3-methyl ether (28) and15,16-secoestra-1,3,5-trien-3-ol (29)

A suspension of 0.100 g of 3 in 10 ml of diethylene glycol and 1.0 ml of64% hydrazine hydrate containing 0.2 g of potassium hydroxide was heatedslowly (1.0 hr) to 200° C. A distillation head was used to collect thedistillate at 110°-125° C. over 3.0 hr. The reaction Was then heated foran additional 4 hr at 200° C., cooled poured into water, and extractedwith ether. The ether solution was washed with water, 4% hydrochloricacid, and water, then was dried over magnesium sulfate and evaporated atreduced pressure to afford 0.071 g of crude product. The crude productwas purified by thick-plate chromatography using a 1,000-μ thick platedeveloped in 10% tetrahydrofuran/hexane. Elution with ethyl acetate gavetwo fractions. Fraction. 1 contained 0.020 g of 28 and fraction 2, 0.028g of 29.

Anal. Mass Spec. for compound C₁₉ H₂₈ O₁ : Calcd., 272; found, 272. Forcompound 29, CI8H260I Calcd., 258; found, 258.

The same reaction conditions were used except that 7.0 g of 3, 150 ml ofethylene glycol, 70.0 ml of 64% hydrazine hydrate, and 10 g of potassiumhydroxide were used to afford 6.2 g of product 29. Recrystallizationfrom hexane afforded pure 29; mp 132°-133° C.

Anal. Hi. Res. Mass Spec. for compound 29, C₁₈ H₂₆ O₁ : Calcd.,258.1984; found, 258.2010.

(b.) 15,16-Secoestra-1,3,5(10)-triene, 3-methyl ether (28)

A suspension of 5.1 g of 28 (as obtained in the preceding step) in 150ml of acetone containing 5.0 g of potassium carbonate and 1.5 ml ofmethyl iodide was stirred at room temperature for 18 hr. The reactionmixture was poured into water and extracted with ether. The ethersolution was washed with water several times, then dried over magnesiumsulfate and evaporated at reduced pressure to afford 5.2 g of 28.Recrystallization from methanol afforded pure 28; mp 69°-70° C.

Anal. Hi. Res. Mass Spec. for compound 28, C₁₉ H₂₈ O: Calcd., 272.2140;found, 272.2129.

EXAMPLE 9

Synthesis of 15,16-seco-19-norandrosta-4-en-3-one (30) ##STR15##

To a solution of 350 ml of ammonia at -78° C. (dry ice-acetone) wasadded 2.57 g of lithium wire, washed with hexane. After 1.0 hr, 5.0 g of28 in a mixture of 75 ml. of ether and 15 ml of absolute ethanol wasadded to the dark blue ammonia-lithium solution at -78° C. The reactionwas stirred at -78° C. for an additional 2 hr while the dark blue colorremained. The reaction was quenched with the slow addition of 200 ml ofethanol. The solution was allowed to warm to room temperature, and theammonia was evaporated over 18 hr. The white solid residue was dissolvedin ether and water, dried over sodium sulfate, and evaporated at reducedpressure to yield 4.2 g of an oil.

To a suspension of 4.2 g of the preceding oil in 150 ml of methanol wasadded dropwise 1.0 ml of concentrated hydrochloric acid. The reactionwas stirred at room temperature for 18 hr. The methanol was evaporatedto half its volume at reduced pressure and then poured into water. Themilky suspension was extracted with ether. The ether solution was washedwith water, dried over sodium sulfate, and evaporated to dryness atreduced pressure to afford 4.1 g of crude material. The crude materialwas purified on HPLC using 10% ethyl acetate and hexane, to afford 3.1 gof pure 15,16-seco-19-norandrosta-4-en-3-one (30). An analytical samplewas obtained by recrystallization from methanol; mp 96°-97° C.

Anal. Hi. Res. Mass Spec. for compound 30, C₁₈ H₂₈ O: Calcd., 260.2128;found, 260.2140.

Example 10

This example describes the preparation of15,16-seco-19-norandrosta-4,6-diene-3-one (34) according to Scheme 8:##STR16##

(a.) 7β-Bromo-15,16-seco-19-norandrosta-4-en-3-one (32)

A solution of 2.15 g of 32 in 1.0 ml of acetic anhydride and 20.0 ml offreshly distilled acetyl chloride was refluxed for 4.0 hr. The solventwas removed at reduced pressure and the resulting oil was trituratedwith cold, aqueous sodium bicarbonate and ice water. After standing at0°-10° C. for 18 hr, the white solid was collected by filtration and airdried for 18 hr. The solid was dissolved in ether and dried overmagnesium sulfate, and the ether was evaporated at reduced pressure toafford 2.17 g of 31.

Anal. Hi. Res. Mass Spec. for compound 31, C₂₀ H₃₀ O₂ : Calcd., 302;Found, 302.

To a solution of 2.17 g of 31 in 100 ml of acetone and 20 ml of watercontaining 3.0 ml of acetic acid, 1.4 ml of pyridine, and 2.81 g ofsodium acetate at 0°-5° C. (ice water bath) was added 1.42 g ofN-bromosuccinimide (recrystallized from water and dried overconcentrated sulfuric acid at 0.01 mm Hg for three days). The reactionwas stirred at 0°-5° C. for 3.0 hr shielded from the light with aluminumfoil. The reaction mixture was poured into cold, saturated sodiumchloride and extracted with ether. The ether solution was washed with.saturated sodium chloride, dried over magnesium sulfate, and evaporatedat reduced pressure o afford 2.6 g of 32. Compound 32 was positive inthe Beilstein test and was not further purified.

Anal. Mass Spec. for compound 32, C₁₈ H₂₇ O Br: Calcd., 338; found, 338.

(b.) 15,16-Seco-19-norandrosta-4.6-diene-3-one (33)

The bromoenone 32 was dissolved in 30 ml of dimethylformamide and addedto a boiling suspension of 2.5 g of lithium bromide and 2.5 g of lithiumcarbonate in 100 ml of dimethylformamide. The suspension was refluxedfor 1.0 hr, then cooled and filtered. The filtrate was poured into anice-water solution, and the mixture was extracted with ether. The ethersolution was washed with 4% sodium hydroxide, water, and saturatedsodium chloride. The ether solution was dried over magnesium sulfate andevaporated at reduced pressure to afford 1.87 g of 33. The mixture waspurified on a Waters Prep 500 chromatograph using 10% ethyl acetate/hexane as the eluent, to afford 1.4 g of pure 33.

Anal. Hi. Res. Mass Spec. for compound 33, C₁₈ H₂₆ O: Calcd., 258.1984;found, 258.1984. PG,53

Example 11

This example describes the synthesis of17α-acetoxy-15,16-seco-19-norandrosta-4-en-3-one (35) according toScheme 9: ##STR17##

To a suspension of 11.16 g of 6 in 1.0 L of methanol was added dropwise3.0 ml of concentrated hydrochloric acid. The reaction was stirred atroom temperature for 18 hr. The methanol was evaporated to half itsvolume at reduced pressure and then poured into water. The milkysuspension was extracted with ether. The ether solution was washed withwater, dried over sodium sulfate, and evaporated to dryness at reducedpressure to afford 9.8 g of crude products 7 and 34. The crude productswere crystallized from ether to yield 5.5 g of pure 7. The remainingmaterial was purified on preparative HPLC, using 10% ethylacetate/chloroform, to afford 1.4 g of 34.

A solution of 0.700 g of 34 in 10 ml of pyridine and 1.0 ml of aceticanhydride was stirred at room temperature for 18 hr. The reactionmixture was poured into ether/water and the organic phase was separated.The aqueous phase was extracted several times with ether. The ethersolutions were combined, washed with water, 4%. hydrochloric acid, andwater. The ether solution was dried over magnesium sulfate andevaporated at reduced pressure to yield 0.728 g of 35 as a glass. Asimilar run using 0.300 g of 34 afforded 0.298 g of product 35.

Anal. Hi. Res. Mass Spec. for compound 35, C₂₀ H₃₀ O₃ : Calcd.,318.2195; found, 318.2217.

Example 12

This example describes the synthesis of17β-cyclobutyl-carboxylate-15,16-seco-19-norandrosta-4-en-3-one (36) asin Scheme 10: ##STR18##

To a solution of 0.100 g of 7 in 5.0 ml of pyridine was added, dropwiseat 0°-5° C. (ice-water bath), 0.22 ml of cyclobutanecarboxylic acidchloride. The reaction was allowed to warm to room temperature andstirred for 18 hr. Then the reaction was poured into water and extractedwith ether. The ether solution was washed with water, 4% sodiumhydroxide, 4% hydrochloric acid, and water. The ether solution was driedover magnesium sulfate and evaporated at reduced pressure to afford0.121 g of crude 36. The crude product was purified by thick-platechromatography using 25% THF/hexane, to give 0.017 g of pure 36.

Example 13

This example describes the preparation of17β-(3',5'-dinitrobenzoate)-15,16-seco-19-norandrosta-4-en-3-one (37) asshown in Scheme 11: ##STR19##

To a solution of 0.100 g of in 5.0 ml of pyridine was added 0.094 g of3,5-dinitrobenzoyl chloride. The reaction was stirred at roomtemperature for 18 hr. The reaction was then poured into water andextracted with ether. The ether solutions were combined and washed withwater, saturated sodium bicarbonate, and water. The washed ethersolution was dried over magnesium sulfate and evaporated at reducedpressure to afford 0.150 g of crude product 37. The crude product waspurified by thick-plate chromatography, using 25% THF/hexane on a 2000-μSiGF thick plate, to give 0.027 g of pure 37.

Example 14

This example is directed to the synthesis of17β-(2'-furoate)-15,16-seco-19-norandrosta-4-en-3-one (38) as shown inReaction Scheme 12: ##STR20##

To a solution of 1.00 g of 7 in 30 ml of pyridine was added 0.04 ml of2-furoyl chloride. The reaction was stirred at room temperature for 18hr and then was poured into water and extracted with ether. The ethersolutions were combined and washed with water, saturated sodiumbicarbonate, and water. The ether solution was dried over magnesiumsulfate and evaporated at reduced pressure to afford 0.980 g of crudeproduct 38. The crude product was triturated from ether to afford 0.501g of pure 38; mp 119°-120° C.

Anal. Hi. Res. Mass Spec. for compound 38, C₂₃ H₃₀ O₄ : Calcd.,370.2139; found 370.2144.

Example 15

This example describes preparation of 2α- and 2β-methyl derivatives via17-tetrahydropyranyl ether intermediates as shown in Scheme 13.##STR21##

(a.) 17β-Hydroxy-15,16-seco-19-norandrosta-4-en-one-17-tetrahydropyranylether (39)

In a flame-dried flask under argon was dissolved 8.28 g of (7) in 300 mlof dry methylene chloride (dried over molecular sieves, 4 Å). To thesolution was added 0.080 g of p-toluenesulfonic acid monohydrate, andthe mixture was cooled to ice-water temperature. Then 8 ml ofdihydropyran was added and the mixture was stirred under argon atice-water temperature for 2 hr. Solid sodium bicarbonate (approximately5 g) was added and the stirring was continued for 30 minutes while thesolution warmed to room temperature. Dilution with 300 ml of ether,filtration through a Florisil (MCB 60-200 mesh), 600 g, 3-in. diametercolumn, and evaporation of the eluent yielded 6.82 g of the product 39.Further elution with 600 ml of methylene chloride-ether (50:50) yieldedanother 4.07 g of 39 for a total combined yield of 10.9 g.

(b.) 17β-Hydroxy-2β-methyl-15,16-seco-19-norandrosta-4-en-3-one-17-tetrahydropyranyl ether (40)

Into a flame-dried reaction flask under argon was introduced 25 ml ofdry tetrahydrofuran (dried by distillation from methyl magnesium bromideand storage over type 4 Å molecular sieves) and a small amount of2,2-dipyridyl was added. Next, 1.57 M butyllithium in hexane was addeduntil the solution turned reddish brown and the color persisted (atwhich time approximately 0.2 ml of the butyllithium solution had beenadded). 10.3 ml of the butyllithium solution was then added. The mixturewas cooled to ice-water temperature, 3.79 ml of freshly distilleddiisopropylamine was added, and the solution was stirred for 15 min. Themixture was cooled to between -75° C. and -80° C. (dry ice-acetate bath)and a solution of 4.0 g of 39 in 60 ml of dry tetrahydrofuran was addeddropwise while the color of the reaction mixture was observed (theoriginal reddish-brown color persisted after the addition of the steroidsolution). The mixture was stirred at between -75° C. and -80° C. for 25min, 10.2 ml of methyl iodide was added, the solution was allowed towarm to room temperature, and stirring was continued for 1 hr. Themixture was then added to saline water and the precipitate was extractedwith ether. The combined ether extract was washed with saline and water,dried over sodium sulfate, and evaporated to dryness at reducedpressure, yielding 4 g of product 40, which was used in the followingstep without further purification.

(c.) 17β-hydroxy-2β-methyl-15,16-seco-19-norandrosta-4-en-3-one (41)

Steroid 40 (4.0 g) was partially dissolved in 75 ml of 90% aqueousmethanol and 30 ml of methylene chloride. Then 0.75 ml of concentratedhydrochloric acid was added, the mixture was stirred at room temperaturefor 2.5 hr. An additional 1.5 ml of concentrated hydrochloric acid wasadded and stirring continued for 90 minutes. TLC indicated that thereaction was complete. Most of the solvent was evaporated at reducedpressure at or below room temperature. The milky solution was dilutedwith water and extracted with ether. The combined ether extract waswashed with saline water and with water, and then dried over sodiumsulfate, and was evaporated to dryness at reduced pressure. Thisprocedure afforded 3.06 g of product 41.

(d.) 2β-Methyl-15,16-seco-19-norandrosta-4-en-3,17-dione (42)

Into a flame-dried flask under argon were introduced 6 ml of drymethylene chloride (dried by passing through a Woelm alumina, basic,activity grade Super I column and storage over 4 Å molecular sieves) and1.46 ml of freshly distilled oxalyl chloride. The solution was cooled to-78° (dry ice-acetone bath), and a solution of 2.46 ml of drydimethylsulfoxide (dried over type 4 Å molecular sieves) in 12 ml of drymethylene chloride was added dropwise durinq 2 min. The temperature wasraised to -15° C. (ice-methanol bath) and the mixture stirred for 2 min.A solution of 3.03 g of steroid 41 in 24 ml of dry methylene chloridewas added, the mixture was stirred at 15° C. for 15 min, followed by theaddition of 10.2 ml of freshly distilled triethylamine. After stirringat -15° C. for 5 min, the reaction was allowed to warm to roomtemperature, and stirred for additional 30 min. To the reaction mixturewas added 10 ml of water and additional methylene chloride. Theseparated aqueous layer was washed with methylene chloride. The combinedmethylene chloride extracts were washed with water, dried over sodiumsulfate, and evaporated to dryness at reduced pressure. The residue. (3g) was chromatographed on a Waters 500 preparative HPLC chromatograph ona normal-phase silica gel cartridge, using 5% ethyl acetate-chloroform,and 1.4 g of pure 42 was obtained. One fraction was rechromatographed ona preparative HPLC, 1-inch stainless steel column packed withnormal-phase silica gel. For elution, 10% ethyl acetate-petroleum ether(bp 35°-60° C.) was used. The product 42 was crystallized fromether-hexane to give an analytical sample; mp 100°-101° C.

Anal. Hi. Res. Mass Spec. for compound 42, C₁₉ H₂₈ O₂ : Calcd.,288.2089; found, 288.2065.

(e.) 2α-Methyl-15,16-seco-19-norandrosta-4-en-3,17-dione (43)

Sodium metal (70 mg) was dissolved in 10 ml of absolute methanol underargon at ice-water temperature. A solution of 0.582 g of 42 in 5 ml ofabsolute methanol was added, and the mixture was allowed to warm to roomtemperature and then stirred for 16 hr. TLC indicated the presence ofstarting material. Additional sodium methoxide (0.040 g) was added andthe mixture was stirred for 4 hr, after which TLC indicated only a smallamount of starting material. The mixture was added to saline water andthe precipitate was extracted with ether. The combined ether extractswere washed with water, dried over sodium sulfate, and evaporated todryness at reduced pressure. The crude residue (0.552 g) waschromatographed on a Waters 500 preparative HPLC chromatograph, using a1-inch stainless steel column filled with normal-phase silica gel.Elution with 10% ethyl acetate-petroleum ether (bp 35°-60° C.) yielded0.210 g of pure compound 43; mp 102°-103° C.

Anal. Hi. Res. Mass Spec. for compound 43, C₁₉ H₂₈ O₂ : Calcd.,288.2089; found, 288.2079.

EXAMPLE 16

This example describes the synthesis of a number of13α-15,16-seco-progestins from17-acetamido-3-methoxy-13αestra-1,3,5(10)-16-tetraene as shown in Scheme14. ##STR22##

(a.) 3-Methoxy-13α-estra-1,3,5(10)-triene-17-one (45)

To a solution of 15.5 g of17-acetamido-3-methoxy-13α-estra-1,3,5(10)-16-tetraene (44); reported byD. H. R. Barton (R. B. Boar et al., J. Chem. Soc. Perkin I, 2163 (1977))in 1200 ml of methanol was added 360 ml of 2N hydrochloric acid. Thereaction mixture was refluxed for 1 hr. The methanol was evaporated atreduced pressure and then poured into water and ether. The organic phasewas separated and the aqueous phase was extracted with additional ether.The ether fractions were combined, washed with water, dried over sodiumsulfate, and evaporated at reduced pressure to afford 12.4 g of 45. Ananalytical sample was obtained by recrystallization from methanol; mp128°-131° C., lit. mp 130°-133° C.

(b.) 3-Methoxy-16,17-seco-13α-estra-1.3.5(10)-triene-16,17-dioic aciddimethylester (46)

A solution of sodium methoxide was prepared by dissolving 7.04 g ofsodium in 1.54 ml of methanol. To this solution was added 10.0 g of 45,and the mixture was stirred for 1 hr to obtain a finely dividedsuspension. After cooling of the suspension to 0°-b 5° C. (ice bath),dry air was bubbled to obtain a saturated solution. (Dry air wasobtained by first bubbling air into concentrated sulfuric acid, thenpassing it through a drying tube containing, in order: potassiumhydroxide pellets, drierite, and calcium chloride.) A solution of 17.88g of iodine in 161 ml of methanol was added dropwise (30 min) while thedry air was being bubbled in. After 3.0 hr of stirring at 5° C., theaeration and stirring were stopped and the flask was stored at 5° C. for18 hr. The resulting yellow solution was acidified to approximately pH 3with concentrated hydrochloric acid. The methanol was evaporated atreduced pressure to approximately 200 ml. The residue was taken up inether and water, and the organic phase was separated. The aqueous phasewas extracted several times with additional ether, and the etherextracts were combined. The organic phase was washed with water, 10%sodium thiosulfate, and water. The ether was extracted with 4% sodiumhydroxide. The ether solution was again washed with 10% sodiumthiosulfate and water, dried over sodium sulfate, and evaporated toyield 6.194 g of diester (46). The sodium hydroxide extract wasacidified with concentrated hydrochloric acid and extracted with ether.The ether solution was washed with water, dried over sodium sulfate, andevaporated at reduced pressure to yield 6.326 g of crude monoester(46A). The diester (46) was purified by thick-plate chromatography andrecrystallized from methanol to afford pure (46), mp 92°-93° C.

Anal. Hi. Res. Mass Spec. for compound 46, C₂₁ H₂₈ O₅ : Calcd.,360.1939; found, 360.1937. Calcd.: C, 69.98; H, 7.83. Found: C, 69.79;H, 8.04.

(c.) 3-Methoxy-15,16-seco-13α-estra-1,3,5(10)-triene-16,17-dioic aciddimethylester (46)

A solution of 6.4 g of (46A) in 50.0 ml of DMA containing 3.2 g ofsodium bicarbonate and 3.0 ml of methyl iodide was stirred at roomtemperature for 18 hr. The reaction was poured into ether/water. Theether solution was separated, washed with 4% sodium hydroxide and water,dried over magnesium sulfate, and evaporated at reduced pressure toafford 6.483 g of 46.

(d.) 3-Methoxy-16,17-seco-13α-estra-1,3,5(10)-trien-16,17-dioic acid17-methyl ester (47)

To a warm solution of 1.0 g of 46 in 50 ml of methanol was added 1.28 gof potassium hydroxide in 50 ml of water. The solution was refluxed for4 hr and then cooled. The methanol was evaporated to 10 ml and pouredinto water. The aqueous phase was extracted with ether. The ether waswashed with water, dried over sodium sulfate, and evaporated at reducedpressure to yield 0.132 g of unreacted 46. The aqueous phases werecombined, acidified With 18% hydrochloric acid, and extracted withether. The ether solution was Washed with water, dried over sodiumsulfate, and evaporated at reduced pressure to yield 0.759 g of product47. An analytical sample was obtained by ,thick-plate chromatography,using 35% tetrahydrofuran hexane and eluting with ethyl acetate.Recrystallization of 47 from hexane/acetone afforded pure 47; mp131°-132° C.

Anal. Hi. Res. Mass Spec. for compound 47, C₂₀ H₂₆ O₅ : Calcd.,346.1780; found, 346.1809.

(e.) 3-Methoxy-16,17-seco-13α-estra-1,3,5(10)-triene-16,17-dioic acid16-acid chloride 17-methyl ester. (48)

To 125 ml of dry benzene (dried over molecular sieves, Aldrich type 4 Å)was added 6.3 g of 47. To the resulting solution, under argon, 6.2 ml offreshly distilled oxalyl chloride was added in two portions. Thereaction mixture was then stirred at room temperature for 20 hr. Thesolvent and the excess oxalyl chloride were distilled off on a rotaryevaporator. The residue 48 (6.4 g) was used in the following stepwithout further purification.

(f.) 3-Methoxy-16,17-seco-13α-estra-1,3,5(10)-triene-16,17-dioic acid16-t-butyl perester 17-methyl ester (49)

To 122 ml of dry benzene (dried over molecular sieves, Aldrich, Type 4Å), was added 6.4 g of 48 from the preceding step. The solution wascooled in a cold-water bath to approximately 10° C. To the mixture,under argon, was added a mixture of 6.14 ml of freshly distilledtert-butylhydroperoxide and 13.46 ml of dry pyridine (dried overmolecular sieves, Aldrich, Type 4 Å). The cooling bath was removed, themixture was allowed to warm to room temperature, and then was stirredfor 2.5 hr. The solution was added to saturated sodium chloride solutionand the organic layer was diluted with ether. The layers were separatedand the aqueous layer was washed twice with ether. The combined organicextract was washed with 3% hydrochloric acid solution, 10% potassiumhydroxide solution, and twice with saturated sodium chloride solution.The solution was then concentrated in vacuo to a viscous residue (7.4g). The residue contained some impurities that did not interfere in thefollowing reaction; therefore, the mixture 49 was used in the followingstep without further purification.

(g.) 3-Methoxy-16,17-seco-16-nor-13α-estra-1,3,5(10)-triene-17-oic acidmethyl ester (50)

A solution of 7.4 g of the residue 49 from the preceding reaction in 180ml of freshly distilled cumene was purged with argon for 1 hr and wasthen heated to reflux temperature. The solution was heated at refluxtemperature for 1 hr and then the solvent was distilled off in vacuo toafford 7.04 g of residue. The residue was chromatographed on a Waters500 preparative HPLC chromatograph. The product, compound 50, was elutedoff with 10% ethyl acetate/ petroleum ether (bp 35°-60° C.). Thisprocedure afforded 2.14 g of steroid 50.

Anal. Hi. Res. Mass Spec. for compound 50, C₁₉ H₂₆ O₃ : Calcd.,302.1882; found, 302.1879.

(h.) 3-Methoxy-15,16-seco-13α-estra-1,3,5(10)-triene-16-one (51)

Under argon, 1.59 g of steroid 50 was dissolved in 21 ml of drytetrahydrofuran (dried by distillation of methylmagnesium bromide andstorage over molecular sieves, Aldrich type 4 Å). To the solution wasadded 1.47 ml of dry triethylamine (dried by passing it through a columnof Woelm alumina, basic, activity grade Super I). Then 10.5 ml of 3 Mmethylmagnesium bromide was added. The mixture was stirred at roomtemperature for 120 hr and then added to 3% hydrochloric acid solution.The products were extracted into three portions of ether. The combinedether extract was washed twice with water, dried over sodium sulfate,and evaporated to dryness at reduced pressure. A colorless oil (1.44 g)was obtained. The residue was chromatographed on a Waters 500preparative HPLC chromatograph, using a 1-inch stainless steel columnpacked with normal-phase silica gel. The product was eluted off with 5%ethyl acetate/petroleum ether. This procedure afforded 0.527 g ofcompound 51.

Anal. Hi. Res. Mass Spec. of compound 51 C₁₉ H₂₆ O₆ : Calcd., 286.1933;found, 286.1918.

(i.) 3-Methoxy-17β-hydroxy-15,16-seco-13α-estra-1,3,5(10)-triene (52)

A solution of 0.695 g of steroid 51 in 40 ml of absolute methanol wascooled in an ice-water bath to 0° C. Then 0.695 g of sodium borohydridewas added to the solution in approximately 50 mg portions. The solutionwas stirred at ice-water temperature for 20 min and then poured into icewater. The precipitate was extracted into three portions of ether. Theether solution was washed three times with saturated sodium chloridesolution, dried over sodium sulfate, and evaporated to dryness atreduced pressure. The oily residue, 0.634 g of compound 52, solidifiedon standing. The residue was used in the following step without furtherpurification.

(j.) 17β-Hydroxy-15,16-seco-13α-estra-4-en-3-one (53)

Under argon, 60 ml of liquid ammonia was condensed at -78° C. (dryice-acetone bath). Lithium wire (152 mg), cut into small pieces, wasadded and the mixture was stirred for 5 min. A solution of 0.634 g of 52in 10 ml of dry THF (dried by distillation from methylmagnesium bromideand storage over molecular sieves, Aldrich 4 Å) was added and themixture stirred at -78° C. for 45 min. Then a mixture of 6 ml ofabsolute ethyl alcohol and 4 ml of dry THF was added. The cooling bathwas removed and the blue color discharged after 15 min. The ammonia wasallowed to evaporate and the residual solution was diluted first withether and then with water. The layers were separated and the aqueouslayer was washed with ether. The combined ether extract was washed withwater, dried over sodium sulfate, and evaporated to dryness at reducedpressure to afford 0.622 g of compound 53. The residue was homogeneouson thin-layer chromatographic analysis and was used in the followingstep without further purification.

The residue from the previous reaction, compound 53, was dissolved in 10ml of absolute methanol and 0.5 ml. of water. Then 0.25 ml ofconcentrated hydrochloric acid was added and the mixture was heated toreflux temperature. After 20 min of gentle reflux, the solution wascooled to room temperature and neutralized with solid sodium acetate.Then the mixture was added to saturated sodium chloride solution andextracted into three portions of ether. The combined ether extract waswashed twice with water, dried over sodium sulfate, and evaporated todryness at reduced pressure to afford 0.945 g of compound 54, an oilthat solidified on standing.

(k.) 15,16-Seco-13α-estra-4-en-3,17-dione (55)

To a solution of 0.490 g of 54 in 50 ml of acetone at 0° C. (ice-waterbath), with nitrogen being bubbled through the solution, was addeddropwise Jones reagent until an orange-green color remained. Isopropanolwas then added to quench excess Jones reagent. The acetone wasevaporated at reduced pressure and the resulting residue was dissolvedin ether and water. The ether solution was evaporated at reducedpressure to afford 0.425 g of crude product. The crude product waspurified by thick-plate chromatography, using 25% THF/hexane and elutionwith ethyl acetate. Recrystallization from hexane afforded 0.075 g ofpure 55.

Anal. Mass Spec. for 55, C₁₈ H₂ O₂ : Calcd., 274.1933; found, 274.1930.

Example 17 ##STR23## (a.)17β-Acetoxy-15,16-seco-19-nor-5α-androstan-3-one (56)

Into a flame-dried flask under argon, 300 ml of liquid ammonia wascondensed at dry ice-acetone temperature (-75° to -80° C.). To theammonia, 0.759 g of lithium wire was added. After the lithium dissolved,there was added a solution of 3.37 g of 8 in 100 ml of dry THF (dried bydistillation from methyl magnesium bromide and stored over 4 Å molecularsieves). The blue solution was stirred under argon at -75° C. for 1.0hr. 1,2-dibromoethane was added dropwise to the solution until all theblue color had discharged. The ammonia was allowed to evaporate onremoval of the cold bath. The residue was taken up in ether and salinewater. The layers were separated and the aqueous layer was extractedwith ether.. The combined ether extract was washed with water, driedover MgSO₄, and concentrated to dryness at reduced pressure. The cruderesidue (3.98 g) was used in the following reaction without furtherpurification.

The above mixture (3.98 g) was dissolved in 15 ml of dry pyridine (driedover KOH). To the solution, 4.0 ml of acetic anhydride was added and themixture was stirred under argon at room temperature for 18 hr. Theresidue was dissolved in ether and water. The layers were separated andthe aqueous layer was extracted with ether. The combined ether extractwas washed with water, dried over MgSO₄, and evaporated to dryness atreduced pressure. The crude product (4.15 g) was purified by HPLC usinga Waters Prep 500 with 8% ethyl acetate/petroleum ether. Evaporation atreduced pressure yielded 2.06 g of pure 56; mp 105°-107° C.

Anal. Hi. Res. Mass Spec. for 56, C₂₀ H₃₂ O₃ : Calcd., 320.2352; found,320.2351.

(b ) 17β-Acetoxy-15,16-seco-19-nor-5α-androstan-3ε-ol (57 )

To solution of 2.05 g of 56 in 200 ml of methanol at 0° C. (ice/waterbath) was added 0.266 g of sodium borohydride in 0.075 g portions. Thereaction was stirred for 2.0 hr at 0° C. and then quenched by the slowaddition of 0.5 ml of acetic acid. The methanol was evaporated atreduced pressure and the resulting residue dissolved in ether and water.The ether solution was separated, washed with several portions of water,dried over magnesium sulfate, and evaporated at reduced pressure toafford 1.32 g of a C-3 mixture of β- and α-hydroxyls.

(c.) 17β-Acetoxy-15,16-seco-19-nor-5α-androstan-3-ol tosylate (58)

To a solution of 1.32 g of 57 in 15 ml of dry pyridine (dried over KOH)was added 5.0 g of tosyl chloride. The reaction was stirred at roomtemperature for 18 hr and then poured into water and extracted withether. The ether solution was washed with water, dried over magnesiumsulfate, and evaporated at reduced pressure to yield 2.24 g of crude 58.

(d.) 17β-Acetoxy-15,16-seco-19-nor-5α-androsten-2-en (59)

A solution of 2.24 g of 58 in 50 ml of xylene and 50 ml of2,3,6-collidine was refluxed for 3.0 hr. The reaction was cooled andpoured into water. The suspension was extracted with ether. The ethersolution was washed with water, 4% HCl, and water, then dried overmagnesium sulfate and evaporated at reduced pressure to afford 1.91 g ofcrude product. Purification by thickplate chromatography using 20%THF/hexane afforded pure 59, mp 156°-159° C.

Anal Hi. Res. Mass Spec. for 59, C₂₀ H₃₂ O₂ : Calcd., 304.2402; found,304.2407.

The following experimental methods were used in obtaining the data asset forth in Example 18, Table 2.

Progestin, androgen, and estrogen cytosol-binding assays were conductedas follows:

Cytosol-Binding Assays 1. Test for Binding of Steroid toProgesterone-Receptor Protein in Rabbit Uterus

Materials: The materials used in this assay were as follows:Progesterone-1,3,6,7-³ H (105 Ci/mmol), ³ H-promegestone (80 Ci/mmol),and unlabeled promegestone, obtained from New England Nuclear Corp.,Boston, Mass. (The purity of the compounds was guaranteed to be greaterthan 99% at delivery.) Unlabeled progesterone and activated charcoalwere purchased from Sigma Chemical Company, St. Louis, Mo.Scintisol-Complete, was supplied by Isolab Inc., Akron, Ohio.

Preparation of uterine cytosol (see E. M. Ritzen et al., Steroids 21:593(1973) and A. Eisenfeld, Endocrinology 94:803 (1974): Uteri fromimmature New Zealand white female rabbits, weighing about 2 kg each,were chilled in ice immediately upon removal. After the fat was trimmedoff, the uteri were minced and washed for 1 hour in Tris-HCl buffer(0.01 M, pH 8.0, containing 0.001 M EDTA and 0.25 M sucrose) at 4° C.The washed uterine tissue was then homogenized in 2/5 (w/v) volume ofthe same Tris-HCl buffer. The homogenate was centrifuged at 12,000 ×gfor 15 min, and the resulting supernatant was centrifuged again for 1hour at 270,000 x g. Glycerol was added to the final supernatant to givea 45% solution. The prepared cytosol was kept frozen until time of use.The whole procedure was carried out at approximately 4° C. The proteincontent of each prepared cytosol was determined by Biuret reagent.

Binding procedures: For the binding assay, 100 μ of uterine cytosol wasmixed with 0.4 ml of Tris-HCl buffer (0.01 M, pH 8.0, containing 0.001 MEDTA, ³ H-promegestone, and 1 μ of DMSO alone or 1 μl of DMSO pluscompetitors to be tested. The mixtures were incubated at 0°-4° C. for24-hr. At the end of the incubation period, free and bound ³H-progesterone or ³ H-promegestone were separated by charcoalextraction.

Charcoal extraction and scintillation counting: To the incubated mixturewas added 0.5 ml of charcoal solution (300 mg of charcoal and 3 mg ofDextran 40 in 50 ml of Tris-HCl buffer used for homogenizing thetissue). The samples were mixed gently and incubated at 4° C. forexactly 10 min. The mixtures then were centrifuged at 4,000 rpm for 10min in a refrigerated centrifuge. The supernatant containing the bound ³H-progesterone or ³ H-promegestone was transferred quantitatively to acounting vial, and 10 ml of scintillation fluid (Scintisol) was addedfor counting. Counting time was adjusted to give a standard deviation ofless than 10%. The scintillation counter used was either the BeckmanLS-250 model or the Searle Mark III system. The efficiency for tritiumon both counters was between 40 and 50%. The counts obtained for sampleswith competitors relative to those without competitors were calculatedto give the percentage of competition.

2. Test for Binding of Steroids to Androgen-Binding Protein in RatTestes

Materials: The materials used in this assay were as follows:Dihydrotestosterone-1,3-³ H (40 Ci/mmol), obtained from New EnglandNuclear Corp., Boston, Mass. (The purity of the compound was guaranteedto be greater than 98% at delivery.) Unlabeled dihydrotestosterone andactivated charcoal were obtained from Sigma Chemical Company, St. Louis,Missouri. Scintisol-Complete was purchased from Isolab Inc., Akron,Ohio. The animals tested were mature Sprague-Dawley male rats.

Preparation of testicular cytosol: Immediately after the animals weresacrificed, their testes were removed and kept on ice. After the fat wastrimmed off, the testes were minced and homogenized in three volumes of0.01 M Tris-HCl buffer (pH 8.0) containing 1.5 mM EDTA and 2 mM2-mercaptoethanol. The homogenate was centrifuged at 100,000×g for 1 hrin a refrigerated centrifuge. The supernatant was transferred to aseparate tube, and glycerol was added to make a 10% solution. Thesupernatant was then extracted with charcoal to remove the steroids thatwere already bound to the protein. For charcoal extraction, thesupernatant was incubated with charcoal (3 mg/ml supernatant) at 0° C.to 4° C. for 18 hrs. The charcoal was then removed by centrifuging for10 min at 12,000×g. The charcoal-extracted supernatant was kept frozenuntil time of use. Binding procedures: For the binding assay, 0.5 ml oftesticular supernatant was mixed with 5 μl of DMSO containing 0.09 ng(27,500 dpm) of ³ H-dihydro-testosterone and 10 μl of DMSO alone or 10μl of DMSO plus competitors to be tested. The mixtures were incubated at0°-4° C. for 3 hrs; free and bound ³ H-dihydrotestosterone wereseparated by charcoal extraction.

Procedures for charcoal extraction and scintillation counting were thesame as described for the progesterone binding assay.

3. In Vivo Estrogen Uterotropic Assay

Immature rats (18 days old) were assigned randomly to groups of 5 to 10.Treatment by oral intubation was started on the day the animals arrivedand continued once daily for 4 days. On Day 5, vaginal smears wereobtained, and uteri--carefully dissected between precise areas betweenthe cervix and the oviduct--was stripped of fat and connective tissueand then weighed on a torsion balance. Fluid in uteri was expressedbefore weighing. Body weights of rats were recorded on the first day andat autopsy.

Comparison of the semilog dose-response curves for three to four doselevels of an active test compound with those for compounds of knownactivity (e.g., estrone administered sc or ethynyl estradiol givenorally) determined the estrogenic activity.

4. Test for Androgenic Activity

Male 21-day-old rats were castrated upon their arrival. On the followingday, they were distributed randomly in groups of 8. All animals werehoused individually in a rack with 1/2-inch mesh, wire-bottom cages. Thetest compound was given by oral intubation for seven consecutive daysand the test was performed on the day following the last treatment.Ventral prostates, seminal vesicles, and levator ani were freed ofconnective tissue and cleaned as they were being removed. They were thenweighed to the nearest 0.2 mg on a torsion balance. Fluid from seminalvesicles was expressed before weighing. Body weights were recorded onthe first day of injection and at autopsy. The degree of weight increasecaused by the test compound was an indication of its androgenicactivity.

Three or more dose levels of a test compound was compared with threestandard doses of testosterone.

5. Test for Progestational Activity

In the Clauberg test, immature female rabbits weighing 800-1000 g, 3rabbits for each dose, were primed subcutaneously with 0.5 μg estradiolin 1 ml aqueous ethanol solution for 6 days to produce a suitableendometrium. The progestogen was then given subcutaneously in sesame oilfor 7-11 days and the animals killed on day 12. The uterine horns werefixed in formalin, frozen sectioned and stained with haematoxylin andeosin. The degree of endometrial proliferation was estimated on theMcPhail scale.

Example 18

A number of the above tests were carried out on the compounds identifiedin Table 2. In Table 2, the Roman numeral identification system is asset forth earlier herein.

                                      TABLE 2                                     __________________________________________________________________________    Nonradioactive Competitor        RBA (%)                                      __________________________________________________________________________    Promegestone                     194                                          Progesterone                     100                                           ##STR24##                       34                                            ##STR25##                       83                                            ##STR26##                       89                                            ##STR27##                       14                                            ##STR28##                       5.2                                           ##STR29##                       9.4                                           ##STR30##                       9.4                                           ##STR31##                       45                                            ##STR32##                       15                                            ##STR33##                       26                                            ##STR34##                       8.5                                           ##STR35##                       37                                            ##STR36##                       38                                            ##STR37##                       8.6                                           ##STR38##                       <1.4                                          ##STR39##                       <1.4                                          ##STR40##                       71                                            ##STR41##                       28                                            ##STR42##                       7                                             ##STR43##                       25                                           __________________________________________________________________________    Structure                Test     Total Dose                                                                             Potency                            __________________________________________________________________________     ##STR44##               Clauberg 1.0; 10 mg                                                                             10-26%                              ##STR45##               Clauberg (Subc) Antigonadotropic (14 days)                                    Uterotropic Clauberg Oral Androgenic Subc                                     Androgenic Oral Postcoital                                                             0.1, 0.1, 0.4  1, 10 mg 0.67 mg/day 10,                                       100; 1000 μg 1.0 & 10 mg 1.0 mg 1.0                                        & 10 mg 1.0 mg/day subc                                                                200% 122% 0 2.4-6.8% 0 0 10/10                                                pregnant                            ##STR46##               Clauberg Subc                                                                          1.0 & 10 mg                                                                            16-57%                              ##STR47##               Postcoital (0-4 days)                                                                  1.0 mg/day Subc                                                                        9/10 pregnant                       ##STR48##               Clauberg 0.2, 0.4, 0.8 mg                                                                       101                                 ##STR49##               Clauberg 1.0; 10 mg                                                                             8.0% at 10 mg                       ##STR50##               Uterotropic                                                                            1.0; 100 μg                                                                         0                                   ##STR51##               Clauberg          8.0%                                ##STR52##               Clauberg          8.0%                               __________________________________________________________________________

In Table 2, "RBA" represents relative binding affinity, i.e., theconcentration of the compound under evaluation that is required todisplace 50% of the bound radioactivity of promogestone divided by theconcentration of promogestone required to obtain the same displacement.

Under the column "standard" in Table 2, "a" designates that the standardused in the above-described Clauberg test was progesterone. The standardrepresented by "b" is estradiol, while those designated "c," "d" and "e"are ethynylestradiol, testosterone, and levonorgestrel, respectively.

Under the column "in vivo biological test", "f" represents the Claubergassay of T. Miyake at page 135 of "Methods in Hormone Research," vol.II, ed. R. I. Dorfman. (New York: Academic Press, 1962). The androgenicassay performed was that of R. I. Dorfman, also in "Methods in HormoneResearch," vol. II, at page 305. The antigonadotropic assay was carriedout according to the method of E. G. Shipley, id. at page 59.

We claim:
 1. A compound having the formula (Va) or (Vb): ##STR53##wherein R is hydrogen or an acyl group of the formula --(C═O)--Y;Y is anorganic substituent selected from the group consisting of alkyl,alkenyl, alkynyl, cycloalkyl, cycloalkylalkylene, haloalkyl, aryl,haloaryl and arylalkylene; R¹ is selected from the group consisting ofhydrogen, alkyl, alkenyl and alkynyl; R² is selected from the groupconsisting of hydrogen, lower alkyl and cyano.
 2. The compound of claim1 having the formula (Va).
 3. The compound of claim 1 having the formula(Vb).
 4. The compound of claim 2 wherein:R is hydrogen or an acyl groupof the formula --(C═O)--Y; Y is selected from the group consisting of:lower alkyl; cycloalkyl; phenyl optionally substituted with 1 or 2 loweralkyl, lower alkoxy, hydroxy and/or nitro substituents; and R¹ ishydrogen or lower alkynyl.
 5. The compound of claim 4 wherein:R is--(C═O)--Y; Y is selected from the group consisting of methyl,cyclobutyl, and 3,5-dinitrophenyl; R¹ is hydrogen or --C═CH; and R² ishydrogen, methyl or cyano.
 6. The compound of claim 3 wherein:R ishydrogen or an acyl group of the formula --(C═O)--Y; Y is selected fromthe group consisting of: lower alkyl; cycloalkyl; phenyl optionallysubstituted with 1 or 2 lower alkyl, lower alkoxy, hydroxy and/or nitrosubstituents; and R¹ is hydrogen or lower alkynyl.
 7. The compound ofclaim 6 wherein:R is --(C═O)--Y; Y is selected from the group consistingof methyl, cyclobutyl, and 3,5-dinitrophenyl; R¹ is hydrogen or--C.tbd.CH; and R² is hydrogen, methyl or cyano.
 8. A pharmaceuticalcomposition useful for treating an endocrine disorder, comprising aneffective amount of the compound of claim 1, 2, 3, 4, 5, 6 or 7 inadmixture with a pharmaceutically acceptable excipient.